SHORT COMMUNICATION DOI: 10.1002/ejoc.201301230 On the Michael Addition of Water to α,β-Unsaturated Ketones Using Amino Acids Verena Resch,*[a] Christiane Seidler,[a] Bi-Shuang Chen,[a] Ian Degeling,[a] and Ulf Hanefeld[a] Keywords: Organocatalysis / Amino acids / Water chemistry / Green chemistry / Michael addition The use of water as a nucleophile for Michael additions is as the best candidate. To obtain a better insight and to deter- still a challenge in organic chemistry. In this report we de- mine the minimum requirements of the catalyst, several scribe the use of amino acids as catalysts for the Michael ad- structurally related compounds were tested. The reaction dition of water to α,β-unsaturated ketones. All 20 proteino- was characterized in terms of conditions and equilibrium. genic amino acids were screened and L-lysine was identified Introduction However, most of the methods furnishing racemic products suffer from complex, cumbersome or expensive preparation The Michael addition of water to α,β-unsaturated of the catalysts. ketones still seems to be a difficult task to achieve by using In the last few years, amino acids have played an impor- chemical methods. Although in nature this reaction is ubiq- tant role in organocatalysis. In particular, proline and its uitous due to its presence in many metabolic cycles, only derivatives have been established as versatile catalysts for a a few methods using non-enzymatic approaches have been variety of different reactions including Michael additions reported. Apart from enzymatic methods using hy- (for selected examples see ref.[9] and for reviews see ref.[10] dratases,[1] for example, fumarase, malease, citraconase and and references cited therein). In some of these methods, the enoyl-CoA hydratase, which are used on an industrial scale, use of water or mixtures of water and organic solvent as the only enantioselective direct catalytic example described reaction media was highlighted, but the addition of water so far was published recently and involved the use of a was not reported. This gives an indication of the difficulty DNA-based catalyst for the hydration of enones in water.[2] of using water as a nucleophile in Michael additions. More- The indirect asymmetric addition of water by hydrobor- over, the use of an amino acid as catalyst and water as both ation, that is a two-step approach, has also been described solvent and nucleophile has so far not been reported. recently using a Taniaphos catalyst.[3] Another method in- We report herein the use of amino acids as catalysts for volving the use of a palladium-wool complex to convert 2- the Michael addition of water to α,β-unsaturated ketones cyclohexen-1-one into 3-hydroxycyclohexanone in a non- (Scheme 1). As a result of its rigid character and its fre- asymmetric fashion has been reported.[4] This method pro- quent use in earlier studies, 2-cyclohexen-1-one (1a)was vides high conversions, however, earlier studies[5] and theo- chosen as the main test substrate. The study focused on l- retical calculations[6] indicated that the reaction equilibrium lysine and l-histidine as the most promising catalysts. lies on the substrate side. Furthermore, the use of acidic Furthermore, the reaction conditions and reaction equilib- ion-exchange resins has been reported[7] and the use of rium were evaluated and different α,β-unsaturated ketones phosphine catalysts has been described for the addition of were tested. To obtain more insight into this reaction, the water and other nucleophiles to α,β-unsaturated ketones.[8] [a] Gebouw voor Scheikunde, Afdeling Biotechnologie, Technische Universiteit Delft, Julianalaan 136, 2628 BL Delft, The Netherlands E-mail: [email protected] [email protected] http://www.bt.tudelft.nl/boc Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201301230. © 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the Scheme 1. Michael addition of water to α,β-unsaturated ketones original work is properly cited. catalysed by lysine. Eur. J. Org. Chem. 2013, 7697–7704 © 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 7697 SHORT COMMUNICATION V. Resch, C. Seidler, B.-S. Chen, I. Degeling, U. Hanefeld minimum requirements of the catalysts were determined by cause the consumption of 2-cyclohexen-1-one without the reducing the number of functional groups on both l-histi- formation of the desired Michael addition product leading dine and l-lysine. to a slight decrease in the mass balance. l-Glutamine showed good activity, but again the mass balance was not l Results and Discussion as good as with -lysine (90% compared with 97 %). Based on these results, l-lysine[11] and l-histidine were further in- We started our investigation by screening the 20 pro- vestigated as two structurally different amino acids. In gene- teinogenic amino acids as potential catalysts for the ral, however, it can be noted that the three basic amino Michael addition of water to 2-cyclohexen-1-one (1a)asthe acids, l-arginine, l-histidine and l-lysine, are among the main test substrate. Because the reactions were carried out best catalysts tested. Also, l-glutamine, an amino acid with in water as the only solvent, the pH needs to be considered a polar uncharged side-chain, showed good catalytic abili- an important parameter. The dissolution of amino acids ties. It should be emphasized that no changes in the pH of alone in water leads to a change in the pH of the reaction the buffer system were ensured after dissolution of the medium. Therefore all reactions were buffered to pH 7 by amino acids. Grouping the amino acids by their structural using sodium phosphate (250 mm). To avoid the presence of and electronic properties showed no clear trend. Also, a additional amines, no nitrogen-containing buffer systems or plot of the pKa values of the α-amino groups against con- salts were used. To compare the rate of the reaction, the version showed no correlation between the reaction rate initial rates (reaction time 3 h) were measured well before and pKa (see the Supporting Information). the maximum yield was reached. Blank reactions contain- Because the reaction takes place in water, the pH of the ing only substrate and the corresponding buffer were per- reaction medium might have an influence on the reaction formed in parallel. rate and should therefore be considered. To quantify this As shown in Figure 1, most of the 20 amino acids cata- effect, the initial rates were measured at different pH values lyse the addition of water to 2-cyclohexen-1-one (1a), except by using sodium phosphate buffer (pH 6–8) and borate for tyrosine, which shows no acceleration compared with buffer (pH 9 and 10) to control the pH of the reaction me- the background reaction caused by buffer alone. This might dium. be caused by the fact that tyrosine is barely soluble in water The results of pH screening clearly show the dependency and therefore no homogeneous reaction system could be of the reaction on the pH of the medium (pH axis, Fig- established. ure 2). The conversion of 2-cyclohexen-1-one into 3-hy- The four fastest reactions were observed with l-histidine, droxycyclohexanone increased with increasing pH. Because l-lysine, l-glutamine and l-cysteine. The fastest reaction OH– ions might be the active species attacking the Michael rate was achieved with l-cysteine, but taking the mass bal- acceptor, the concentration of OH– plays an important role ance into account, this system is not competitive with, for in the reaction rate and therefore higher pH values lead to example, l-lysine. Side-reactions such as polymerization an acceleration of the reaction. In parallel, it can be noted Figure 1. Screening of the 20 proteinogenic amino acids for their ability to catalyse the Michael addition of water to 2-cyclohexen-1-one (1a) yielding 3-hydroxycyclohexanone. The bars represent conversion. The blank reaction is represented by the striped bar. Dots represent the mass balance. 7698 www.eurjoc.org © 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2013, 7697–7704 Michael Addition of Water to α,β-Unsaturated Ketones that by increasing the pH, the mass balance decreases and catalysed (Figure 2), the focus was set on the primary amine more side-reactions occur due to the harsher reaction con- group rather than on the carboxylic acid functionality. Sev- ditions. Here again, polymerization products form, as is evi- eral structurally reduced catalysts based on l-histidine and dent by the change in colour of the reaction mixture; the l-lysine were tested. Decreasing the number of functional colourless reaction mixture turned yellowish over time at groups should indicate which functionalities are involved in pH values higher than 8. the catalysis. On this basis, cadaverine, butylamine, propyl- amine, ethylamine and methylamine were tested as possible truncated l-lysine analogues (Figure 3). Figure 3. Study of the minimum requirement for the catalyst l- lysine: primary amines cadaverine, butylamine, propylamine, ethyl- amine and methylamine were used. The same principle was applied to l-histidine. As pos- sible catalysts, histamine, 4-methyl-1H-imidazole, imidazole and pyrrole were tested. The small amino acids glycine and l-alanine, representing catalysts in which both the primary amine and the carboxylic acid are retained but not the sec- Figure 2. Temperature and pH profile for the addition of water to ond primary amine or imidazole moiety, were included for 2-cyclohexen-1-one (1a).